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Preclinical Studies on the Molecular Basis of Bortezomib Resistance and Modalities to Overcome Resistance in Hematological Malignancies

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

Abstract

The success of the proteasome inhibitor bortezomib for the treatment of multiple myeloma has encouraged its broader use for other hematological malignancies such as lymphomas and acute leukemia. An important feature for the successful implementation of bortezomib in the treatment of acute leukemia would rely on the selection of patients that will benefit. In order to achieve this goal, preclinical studies can help to establish the mechanism(s) of action underlying proteasome inhibition in leukemic cells and recognize possible mechanisms of acquired resistance. This chapter presents an overview about the current knowledge of these mechanisms based on in vitro and ex vivo studies. Moreover, strategies are discussed that have been set up to overcome resistance, e.g., by novel proteasome inhibitors and combinations of bortezomib with other chemotherapeutic drugs. Finally, an update is provided of the ongoing clinical trials investigating the potential benefits of proteasome inhibitors in acute leukemia.

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Abbreviations

5AHQ:

5-Amino-8-hydroxyquinole

ABC:

ATP-binding cassette

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

BCRP:

Breast cancer resistance protein

BTZ:

Bortezomib

CFZ:

Carfilzomib

C-L:

Caspase-like

cP:

Constitutive proteasome

CR:

Complete remission

CT-L:

Chymotrypsin-like

ER:

Endoplasmic reticulum

IGFR:

Insulin-like growth factor receptor

iP:

Immunoproteasome

IRF4:

Interferon regulating factor 4

MDR:

Multidrug resistance

MHC:

Major histocompatibility complex

MM:

Multiple myeloma

MRP:

Multidrug resistance-associated protein

MTT-assay:

MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay

Pgp:

P-glycoprotein

SEM:

Standard error of the mean

T-L:

Trypsin-like

TRAF:

TNF activating factor

WT:

Wild type

References

  1. Inaba H, Greaves M, Mullighan CG (2013) Acute lymphoblastic leukaemia. Lancet 381:1943–1955

    Article  PubMed  Google Scholar 

  2. Creutzig U, van den Heuvel-Eibrink MM, Gibson B et al (2012) Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 120:3187–3205

    Article  PubMed  CAS  Google Scholar 

  3. Kumar CC (2011) Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes Cancer 2:95–107

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Bachas C, Schuurhuis GJ, Hollink IHIM et al (2010) High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: implications for personalized medicine. Blood 116:2752–2758

    Article  PubMed  CAS  Google Scholar 

  5. Bachas C, Schuurhuis GJ, Assaraf YG et al (2012) The role of minor subpopulations within the leukemic blast compartment of AML patients at initial diagnosis in the development of relapse. Leukemia 26:1313–1320

    Article  PubMed  CAS  Google Scholar 

  6. Welch JS, Ley TJ, Link DC et al (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150:264–278

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Kaspers GJL, Zimmermann M, Reinhardt D et al (2013) Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol 31:599–607

    Article  PubMed  CAS  Google Scholar 

  8. Moreau P, Richardson PG, Cavo M et al (2012) Proteasome inhibitors in multiple myeloma: 10 years later. Blood 120:947–959

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Saric T, Graef CI, Goldberg AL (2004) Pathway for degradation of peptides generated by proteasomes: a key role for thimet oligopeptidase and other metallopeptidases. J Biol Chem 279:46723–46732

    Article  PubMed  CAS  Google Scholar 

  10. Drews O, Wildgruber R, Zong C et al (2007) Mammalian proteasome subpopulations with distinct molecular compositions and proteolytic activities. Mol Cell Proteomics 6:2021–2031

    Article  PubMed  CAS  Google Scholar 

  11. Guillaume B, Chapiro J, Stroobant V et al (2010) Two abundant proteasome subtypes that uniquely process some antigens presented by HLA class I molecules. Proc Natl Acad Sci U S A 107:18599–18604

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Kunjappu MJ, Hochstrasser M (2014) Assembly of the 20S proteasome. Biochim Biophys Acta 1843(1):2–12

    Article  PubMed  CAS  Google Scholar 

  13. Groettrup M, Khan S, Schwarz K, Schmidtke G (2001) Interferon-gamma inducible exchanges of 20S proteasome active site subunits: why? Biochimie 83:367–372

    Article  PubMed  CAS  Google Scholar 

  14. Aki M, Shimbara N, Takashina M et al (1994) Interferon-gamma induces different subunit organizations and functional diversity of proteasomes. J Biochem 115:257–269

    PubMed  CAS  Google Scholar 

  15. Altun M, Galardy PJ, Shringarpure R et al (2005) Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. Cancer Res 65:7896–7901

    PubMed  CAS  Google Scholar 

  16. Seifert U, Bialy LP, Ebstein F et al (2010) Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142:613–624

    Article  PubMed  CAS  Google Scholar 

  17. Nathan J, Spinnenhirn V, Schmidtke G et al (2013) Immuno- and constitutive proteasomes do not differ in their abilities to degrade ubiquitinated proteins. Cell 152:1184–1194

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Niewerth D, Franke NE, Jansen G et al (2013) Higher ratio immune vs. constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. Haematologica 98(12):1896–1904

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Bianchi G, Oliva L, Cascio P et al (2009) The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood 113:3040–3049

    Article  PubMed  CAS  Google Scholar 

  20. Niewerth D, Dingjan I, Cloos J et al (2013) Proteasome inhibitors in acute leukemia. Expert Rev Anticancer Ther 13:327–337

    Article  PubMed  CAS  Google Scholar 

  21. Kane RC, Farrell AT, Sridhara R, Pazdur R (2006) United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res 12:2955–2960

    Article  PubMed  CAS  Google Scholar 

  22. Kane RC, Dagher R, Farrell A et al (2007) Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 13:5291–5294

    Article  PubMed  CAS  Google Scholar 

  23. Frankland-Searby S, Bhaumik SR (2012) The 26S proteasome complex: an attractive target for cancer therapy. Biochim Biophys Acta 1825:64–76

    PubMed  CAS  PubMed Central  Google Scholar 

  24. McConkey DJ, Zhu K (2008) Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist Updat 11:164–179

    Article  PubMed  CAS  Google Scholar 

  25. Naujokat C, Sezer O, Zinke H et al (2000) Proteasome inhibitors induce caspase-dependent apoptosis and accumulation leukemic cells. Eur J Hematol 65:221–236

    Article  CAS  Google Scholar 

  26. Nasr R, El-Sabban ME, Karam J-A et al (2005) Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma. Oncogene 24:419–430

    Article  PubMed  CAS  Google Scholar 

  27. Martinon F (2012) Targeting endoplasmic reticulum signaling pathways in cancer. Acta Oncol 51:822–830

    Article  PubMed  CAS  Google Scholar 

  28. Driscoll JJ, De Chowdhury R (2012) Molecular crosstalk between the proteasome, aggresomes and autophagy: translational potential and clinical implications. Cancer Lett 325:147–154

    Article  PubMed  CAS  Google Scholar 

  29. Kincaid EZ, Che JW, York I et al (2012) Mice completely lacking immunoproteasomes show major changes in antigen presentation. Nat Immunol 13:129–135

    Article  CAS  Google Scholar 

  30. Vigneron N, Van den Eynde BJ (2012) Proteasome subtypes and the processing of tumor antigens: increasing antigenic diversity. Curr Opin Hematol 24:84–91

    CAS  Google Scholar 

  31. Oerlemans R, Franke NE, Assaraf YG et al (2008) Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112:2489–2499

    Article  PubMed  CAS  Google Scholar 

  32. Franke NE, Niewerth D, Assaraf YG et al (2012) Impaired bortezomib binding to mutant beta5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia 26:757–768

    Article  PubMed  CAS  Google Scholar 

  33. Li X, Wood TE, Sprangers R et al (2010) Effect of noncompetitive proteasome inhibition on bortezomib resistance. J Natl Cancer Inst 102:1069–1082

    Article  PubMed  CAS  Google Scholar 

  34. Ruckrich T, Kraus M, Gogel J et al (2009) Characterization of the ubiquitin-proteasome system in bortezomib-adapted cells. Leukemia 23:1098–1105

    Article  PubMed  CAS  Google Scholar 

  35. Kraus M, Ruckrich T, Reich M et al (2007) Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells. Leukemia 21:84–92

    Article  PubMed  CAS  Google Scholar 

  36. Busse A, Kraus M, Na IK et al (2008) Sensitivity of tumor cells to proteasome inhibitors is associated with expression levels and composition of proteasome subunits. Cancer 112:659–670

    Article  PubMed  CAS  Google Scholar 

  37. Balsas P, Galan-Malo P, Marzo I, Naval J (2012) Bortezomib resistance in a myeloma cell line is associated to PSMβ5 overexpression and polyploidy. Leuk Res 36:212–218

    Article  PubMed  CAS  Google Scholar 

  38. Lu S, Yang J, Huang C et al (2011) Upregulated expression of the PSMB5 gene may contribute to drug resistance in patient with multiple myeloma when treated with bortezomib-based regimen. Exp Hematol 39:1117–1118

    Article  Google Scholar 

  39. Lü S-Q, Yang J-M, Huang C-M et al (2011) Comparison of protein expression profiles between bortezomib-resistant Jurkat B cells with PSMB5 mutation and their parent cells. J Exp Hematol 19:869–873

    Google Scholar 

  40. Lu S, Chen Z, Yang J et al (2008) Overexpression of the PSMB5 gene contributes to bortezomib resistance in T-lymphoblastic lymphoma/leukemia cells derived from Jurkat line. Exp Hematol 36:1278–1284

    Article  PubMed  CAS  Google Scholar 

  41. Lu S, Yang J, Chen Z et al (2009) Different mutants of PSMB5 confer varying bortezomib resistance in T lymphoblastic lymphoma/leukemia cells derived from the Jurkat cell line. Exp Hematol 37:831–837

    Article  PubMed  Google Scholar 

  42. Ri M, Iida S, Nakashima T et al (2010) Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress. Leukemia 24:1506–1512

    Article  PubMed  CAS  Google Scholar 

  43. Verbrugge SE, Al M, Assaraf YG et al (2013) Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors. Exp Hematol Oncol 2:2

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. De Wilt LH, Jansen G, Assaraf YG et al (2012) Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer. Biochem Pharmacol 83:207–217

    Article  PubMed  Google Scholar 

  45. Suzuki E, Demo S, Deu E et al (2011) Molecular mechanisms of bortezomib resistant adenocarcinoma cells. PLoS One 6:e27996

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Groll M, Berkers CR, Ploegh HL, Ovaa H (2006) Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 14:451–456

    Article  PubMed  CAS  Google Scholar 

  47. Borissenko L, Groll M (2007) Diversity of proteasomal missions: fine tuning of the immune response. Biol Chem 388:947–955

    Article  PubMed  CAS  Google Scholar 

  48. Kale AJ, McGlinchey RP, Lechner A, Moore BS (2011) Bacterial self-resistance to the natural proteasome inhibitor salinosporamide A. ACS Chem Biol 6:1257–1264

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Kale AJ, Moore BS (2012) Molecular mechanisms of acquired proteasome inhibitor resistance. J Med Chem 55:10317–10327

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Lichter DI, Danaee H, Pickard MD et al (2012) Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone. Blood 120:4513–4516

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Gillet J-P, Gottesman MM (2012) Overcoming multidrug resistance in cancer: 35 years after the discovery of ABCB1. Drug Resist Updat 15:2–4

    Article  PubMed  Google Scholar 

  52. Minderman H, Zhou Y, O’Loughlin KL, Baer MR (2007) Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Cancer Chemother Pharmacol 60:245–255

    Article  PubMed  CAS  Google Scholar 

  53. Verbrugge SE, Assaraf YG, Dijkmans BC et al (2012) Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with. J Pharmacol Exp Ther 341:174–182

    Article  PubMed  CAS  Google Scholar 

  54. O’Connor R, Ooi MG, Meiller J et al (2013) The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias. Cancer Chemother Pharmacol 71:1357–1368

    Article  PubMed  Google Scholar 

  55. Ao L, Wu Y, Kim D et al (2012) Development of peptide-based reversing agents for p-glycoprotein-mediated resistance to carfilzomib. Mol Pharm 9(8):2197–2205

    PubMed  CAS  PubMed Central  Google Scholar 

  56. Gutman D, Morales A, Boise LH (2009) Acquisition of a multidrug-resistant phenotype with a proteasome inhibitor in multiple myeloma. Leukemia 23:2181–2183

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Zhou H-J, Aujay M, Bennett MK et al (2009) Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem 52: 3028–3038

    Article  PubMed  CAS  Google Scholar 

  58. Kuhn DJ, Berkova Z, Jones RJ et al (2012) Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma. Blood 120:3260–3270

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Pérez-Galán P, Mora-Jensen H, Weniger MA et al (2011) Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation. Blood 117:542–552

    Article  PubMed  PubMed Central  Google Scholar 

  60. Liu H, Tamashiro S, Baritaki S et al (2012) TRAF6 activation in multiple myeloma: a potential therapeutic target. Clin Lymphoma Myeloma Leuk 12:155–163

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Fang J, Rhyasen G, Bolanos L et al (2012) Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1. Blood 120:858–867

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Dick LR, Fleming PE (2010) Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today 15:243–249

    Article  PubMed  CAS  Google Scholar 

  63. Kortuem KM, Stewart K (2013) Carfilzomib. Blood 121:893–897

    Article  PubMed  CAS  Google Scholar 

  64. Kisselev AF, van der Linden WA, Overkleeft HS (2012) Proteasome inhibitors: an expanding army attacking a unique target. Chem Biol 19:99–115

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Orlowski RZ, Kuhn DJ (2008) Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14:1649–1657

    Article  PubMed  CAS  Google Scholar 

  66. Ruschak AM, Slassi M, Kay LE, Schimmer AD (2011) Novel proteasome inhibitors to overcome bortezomib resistance. J Natl Cancer Inst 103:1007–1017

    Article  PubMed  CAS  Google Scholar 

  67. Parlati F, Lee SJ, Aujay M et al (2009) Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 114: 3439–3447

    Article  PubMed  CAS  Google Scholar 

  68. Kuhn DJ, Chen Q, Voorhees PM et al (2007) Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110:3281–3290

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  69. Stapnes C, Doskeland AP, Hatfield K et al (2007) The proteasome inhibitors bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells. Br J Haematol 136:814–828

    Article  PubMed  CAS  Google Scholar 

  70. Chauhan D, Catley L, Li G et al (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8:407–419

    Article  PubMed  CAS  Google Scholar 

  71. Miller CP, Ban K, Dujka ME et al (2007) NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 110:267–277

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  72. Kuhn DJ, Orlowski RZ (2012) The immunoproteasome as a target in hematologic malignancies. Semin Hematol 49:258–262

    Article  PubMed  CAS  Google Scholar 

  73. Muchamuel T, Basler M, Aujay MA et al (2009) A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med 15:781–787

    Article  PubMed  CAS  Google Scholar 

  74. Singh AV, Bandi M, Aujay MA et al (2011) PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7, blocks multiple myeloma cell growth both in vitro and in vivo. Br J Haematol 152:155–163

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. Chauhan D, Tian Z, Zhou B et al (2011) In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 17:5311–5321

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Assouline S, Chang JE, Cheson BD et al (2012) Results of a phase 1 dose-escalation study of once-weekly MLN9708, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. ASH annual meeting 120:3646

    Google Scholar 

  77. Chauhan D, Singh AV, Aujay M et al (2010) A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood 116:4906–4915

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  78. Micel LN, Tentler JJ, Smith PG, Eckhardt GS (2013) Role of ubiquitin ligases and the proteasome in oncogenesis: novel targets for anticancer therapies. J Clin Oncol 31:1231–1238

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  79. Moran-Crusio K, Reavie LB, Aifantis I (2012) Regulation of hematopoietic stem cell fate by the ubiquitin proteasome system. Trends Immunol 33:357–363

    Article  PubMed  CAS  Google Scholar 

  80. Krämer OH, Stauber RH, Bug G et al (2013) SIAH proteins: critical roles in leukemogenesis. Leukemia 27:792–802

    Article  PubMed  Google Scholar 

  81. Swords RT, Kelly KR, Smith PG et al (2010) Brief report Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood 115: 3796–3800

    Article  PubMed  CAS  Google Scholar 

  82. Smith MA, Maris JM, Gorlick R et al (2012) Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer 59:246–253

    Article  PubMed  Google Scholar 

  83. Horton TM, Gannavarapu A, Blaney SM et al (2006) Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother Pharmacol 58:13–23

    Article  PubMed  CAS  Google Scholar 

  84. Sanchez E, Li M, Li J et al (2012) CEP-18770 (delanzomib) in combination with dexamethasone and lenalidomide inhibits the growth of multiple myeloma. Leuk Res 36:1422–1427

    Article  PubMed  CAS  Google Scholar 

  85. Chauhan D, Singh A, Brahmandam M et al (2008) Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 111:1654–1664

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. Kawaguchi Y, Kovacs JJ, McLaurin A et al (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115:727–738

    Article  PubMed  CAS  Google Scholar 

  87. Nie D, Huang K, Yin S et al (2012) Synergistic/additive interaction of valproic acid with bortezomib on proliferation and apoptosis of acute myeloid leukemia cells. Leuk Lymphoma 53:2487–2495

    Article  PubMed  CAS  Google Scholar 

  88. Niewerth D, Franke N, Jansen G et al (2012) Interferon-y-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance of leukemia cell lines harbouring bortezomib-induced mutations in constitutive PSMB5. ASH annual meeting abstracts 120:1346

    Google Scholar 

  89. Horton TM, Pati D, Plon SE et al (2007) A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children’s Oncology Group study. Clin Cancer Res 13:1516–1522

    Article  PubMed  CAS  Google Scholar 

  90. Cortes J, Thomas D, Koller C et al (2004) Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res 10:3371–3376

    Article  PubMed  CAS  Google Scholar 

  91. Faderl S, Rai K, Gribben J et al (2006) Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia. Cancer 107:916–924

    Article  PubMed  CAS  Google Scholar 

  92. Santos FP, Kantarjian H, McConkey D et al (2011) Pilot study of bortezomib for patients with imatinib-refractory chronic myeloid leukemia in chronic or accelerated phase. Clin Lymphoma Myeloma Leuk 11:355–360

    Article  PubMed  CAS  Google Scholar 

  93. Attar EC, De Angelo DJ, Supko JG et al (2008) Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with acute myelogenous leukemia. Clin Cancer Res 14:1446–1454

    Article  PubMed  CAS  Google Scholar 

  94. Blum W, Schwind S, Tarighat SS et al (2012) Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia. Blood 119:6025–6031

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  95. Orlowski RZ, Voorhees PM, Garcia RA et al (2005) Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 105:3058–3065

    Article  PubMed  CAS  Google Scholar 

  96. Brown RE, Bostrom B, Zhang PL (2004) Morphoproteomics and bortezomib/dexamethasone-induced response in relapsed acute lymphoblastic leukemia. Ann Clin Lab Sci 34:203–205

    PubMed  Google Scholar 

  97. Messinger YH, Gaynon PS, Sposto R et al (2012) Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood 120:285–290

    Article  PubMed  CAS  Google Scholar 

  98. Horton TM, Perentesis J, Gamis AS et al (2012) A phase 2 study of bortezomib combined with reinduction chemotherapy in children and young adults with recurrent, refractory or secondary acute myeloid leukemia: a Children’s Oncology Group (COG) study. ASH annual meeting 120:3580

    Google Scholar 

  99. Szczepanek J, Pogorzala M, Konatkowska B et al (2010) Differential ex vivo activity of bortezomib in newly diagnosed paediatric acute lymphoblastic and myeloblastic leukaemia. Anticancer Res 30:2119–2124

    PubMed  CAS  Google Scholar 

  100. Kapoor P, Ramakrishnan V, Rajkumar SV (2012) Bortezomib combination therapy in multiple myeloma. Semin Hematol 49:228–242

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  101. Warlick ED, Cao Q, Miller J (2013) Bortezomib and vorinostat in refractory acute myelogenous leukemia and high-risk myelodysplastic syndromes: produces stable disease but at the cost of high toxicity. Leukemia 27:1789–1791

    Article  PubMed  CAS  Google Scholar 

  102. Wright JJ (2010) Combination therapy of bortezomib with novel targeted agents: an emerging treatment strategy. Clin Cancer Res 16:4094–4104

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Jacqueline Cloos Ph.D. & Denise Niewerth Ph.D.

  2. Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands

    Jacqueline Cloos Ph.D. & Denise Niewerth Ph.D.

  3. Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands

    Gerrit Jansen Ph.D.

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  1. Jacqueline Cloos Ph.D.
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  2. Denise Niewerth Ph.D.
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  3. Gerrit Jansen Ph.D.
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Correspondence to Jacqueline Cloos Ph.D. .

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  1. Wayne State University, Detroit, Michigan, USA

    Q. Ping Dou

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Cloos, J., Niewerth, D., Jansen, G. (2014). Preclinical Studies on the Molecular Basis of Bortezomib Resistance and Modalities to Overcome Resistance in Hematological Malignancies. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_7

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